1. Field of the Invention
The present invention relates to a medicinal patch which continuously delivers a certain amount of oil-soluble drugs through the skin or mucous membranes. More specifically, the present invention relates to a medicinal patch which dissolves the maximum level of drug in the adhesive layer contacting with the skin and delivers percutaneously the necessary amount of drug and enhances the percutaneous penetration of drug.
2. Description of the Prior Art
It has been widely used to deliver drugs (physiologically active agents) through the skin by employing a patch, a sort of percutaneous administrating preparations, for the purpose of the systemic or topical delivery of drugs. These methods of percutaneous administration offers many advantages over the traditional oral administration of drugs. For example, in the method of oral administration, a great level of drug is degraded by the metabolism in the liver prior to exhibiting its efficacy at the target site. However, in the method of percutaneous administration, the efficacy of absorbed drug is not seriously degraded by the metabolism in the liver because the absorbed drug does not pass through the liver before its circulation in the body. Particularly in the case of non-steroidal anti-inflammatory agents, their percutaneous administration gives an advantage of reducing the risk of damage to the gastrointestine which frequently occurs by the oral administration.
Based on the above-mentioned advantages, recently, studies on the transdermal drug delivery system which overcomes the first-pass effect or gastrointestinal damage induced in the oral administration and enhances the effectiveness and safety of drugs have been widely proceeded and, as a result, dermal compositions containing nitroglycerin, scopolamine and the like had been on the market.
In the meanwhile, many drawbacks of the above transdermal drug delivery system have also been indicated in connection with the difficulty in applying it to various drugs. Because the human skin serves as a barrier to the invasion of pathogens and toxic materials, it is highly impermeable. Accordingly, extensive attempts have been made for the purpose of enlarging the utility of transdermal delivery system and enhancing penetration through the skin.
It is possible to reduce the side effects caused by an administration of large amount of drug in a short time by regulating the absorption of the drug. It is also possible to maintain a constant level of drug in blood over a prolonged period by decreasing the frequency of administration.
However, a percutneous administration of drug frequently causes poor bioavailability due to the difficulty of penetration of the drug across the skin. To solve this problem, attempts to increase the absolute amount of drug in a patch to a level of ensuring the percutaneous absorption of necessary amounts have been made. For example, preparations for percutaneous admistration which comprise drug dissolved in bases for patch, ointment, cream and the like to a level exceeding the saturation concentration and dispersed in the form of recrystallized minute particles had been reported. If the patch of this type is applied on the skin surface, the drug dissolved in base is absorbed percutaneously and then, the drug existed in the form of minute particles is gradually dissolved and supplemented the absorbed drug. However, in practical, the drug existed in the form of minute particles is scarcely dissolved in the base and consequently the absorption rate of the drug across the skin is not relatively high.
Alternative methods of enhancing the percutaneous absorption of drug by occlusion have been also attempted. For example, methods for enhancing the percutaneous absorption of active agents by selecting substantially water-impermeable film as a backing layer of patch had been reported. However, these methods also have disadvantages that the sweat may arise skin-irritation and the patch is readily peeled off from the skin by the sweat. In order to eliminate the above problems, a plaster employing highly water-permeable materials such as non-woven fabric or hygroscopic urethane was proposed. However, these plasters have also failed in delivering the required amount of drug across the skin.
To reduce the skin-irritation and improve the feeling of adhesiveness, methods of employing water-soluble vehicle such as gelatin, polyvinylalcohol, dextrin, arabic gum, carboxymethyl cellulose, methylcellulose, hydroxy ethyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium polyacrylate and the like have been also proposed. However, since the patches prepared by the above methods show poor skin-adhesiveness, they can not be applied alone on the skin and must be used together with a fabric applied adhesive and moreover, the efficacy of delivering drug across the skin is not sufficient.
U.S. Pat. No. 4,814,168 disclose a dermal composition suitable for use in the transdermal delivery of drugs, which composition permits a high loading of medicament into the formulation while maintaining acceptable shear, tack and peel as adhesive properties. The composition of the patent comprises a drug, a multi-polymer comprising vinyl acetate and ethylene monomers; a rubber and a tackifying agent.
U.S. Pat. No. 5,176,916 discloses an adhesive comprising a base mainly composed of a hydrophobic polymer in which a medicinal ingredient which is difficult to absorb percutaneously; for example a medicinal ingredient having relatively high hydrophilicity, is incorporated and water as a solubilizer is further contained. According to the patent, water is incorporated as a solubilizer in an amount necessary for making the plaster layer a W/O type.
However, the adhesive of U.S. Pat. No. 5,176,916 fits for relatively highly hydrophilic drugs and is not suitable for oil-soluble drugs, for example non-steroidal anti-inflammatory drugs since it contains water.
In these circumstances, the present inventors have made extensive studies for the purpose of providing a adhesive suitable for oil-soluble drugs which makes it possible to stably release the drug and sustain the pharmacological effects over a long period and as a result thereof found that the above purpose can be accomplished by a adhesive containing multilayered adhesive layer of which each layer has different water absorption capacity.